Metastasis is a late event in cancer development, and is responsible for 90% of deaths from solid tumors. In order to better understand the events leading to the development of metastatic tumors, this proposal will examine the interactions between a metastasis and its host tissue. The specific aims of this proposal are: (1) To determine the involvement of the matrix degrading enzymes, heparanase and cathepsins, in the metastatic invasion of breast cancer cells into the brain, lung, and bone, (2) To determine the necessity of heparanase and cathepsins in the metastatic invasion of breast cancer cells into the brain, and (3) To identify macrophage-derived factors important for the growth or inhibition of metastatic tumors. These aims will be studied through the usage of a xenograft model system in which metastatic cells that home specifically to the brain, lung, and bone will be used to develop tumors in immunocompromised nude mice. Examination of the roles of matrix-degrading enzymes during metastasis will be accomplished by histological analysis of brain, lung, and bone metastases, by treating brain metastases with pharmacological inhibitors of heparanase and cathepsins, and by generating brain metastases in heparanase and cathepsin null immunocompromised mice. Additionally, in vitro assays and a bone marrow transfer protocol will be utilized to determine the contributions of macrophages to the growth of new metastases. This project has relevance to human cancers as it will provide essential insights into the mechanisms of metastasis formation and the contributions of individual stromal and parenchymal cells. These insights can then be used to generate improved and more specific cancer therapies. Advanced cancers often form tumors in distant parts of the body, a process, known as metastasis, that requires cooperation from the normal, healthy tissue around the new tumor. By using an experimental model of metastasis, the interactions between cancer cells and normal cells can be examined, with particular emphasis placed on the enzymes responsible for breaking down the network that holds cells in place, thus making room for the tumor to grow in. Through this study, a better understanding of the mechanisms involved in metastasis will be generated, which should lead to more effective cancer treatments.